Short-Term Intensified Dosage Regimen of Mycophenolic Acid is Associated with Less Acute Rejection in Kidney Transplantation from Donation after Circulatory Death

Abstract

Introduction: Whether an early, short-term, adequate exposure to mycophenolic acid (MPA) under tacrolimus-based immunosuppression regimen in kidney transplantation from donation after circulatory death (DCD) was effective and safe is yet unknown. Material and Methods: The study was a single-center, retrospective, cohort study of DCD transplantation in China. Intensified and standard dosage regimens of enteric-coated mycophenolate sodium (EC-MPS) were week 1, 2,160 vs. 1,440 mg/day. The incidences of biopsy-proven acute rejection (BPAR), delayed graft function, infection, and patient and graft survival were compared between the 2 groups. Results: A total of 209 patients (n = 82 in intensified group and n = 127 in standard group) were enrolled from August 2013 to December 2014. The incidence of BPAR at 12 months was significantly lower in the intensified group as compared to that of the standard group. (2.4 vs. 10.2%, p = 0.035). The mean MPA area under curve (AUC) levels at day 7 was significantly higher in the intensified group than that in the standard group (66.18 ± 35.48 vs. 45.30 ± 23.5 mg·h/L, p < 0.001). MPA AUC levels were significantly decreased in patients with BPAR as compared to those with NO-BPAR. Conclusion: An early, short-term regimen of intensified EC-MPS with tacrolimus increased early MPA exposure and achieved a low rate of BPAR in kidney transplantation from DCD.

Optimizing Mycophenolic Acid Exposure in Kidney Transplant Recipients: Time for Target Concentration Intervention

“…A substantial increase in rejection rates has been reported with an initial MPA AUCt 0-12 <30 mg/L.h and 1 of the following: >3 human leukocyte antigen mismatches, panel reactive antibody >15%, repeat transplant, delayed graft function, or African American descent; 89 if concurrent underexposure to other immunosuppressants 93 or for expanded criteria donation. 97,98 Elsewhere, similar rejection “thresholds” have been reported in contemporary regimen. 41,91 Rapid and effective target concentration attainment could ameliorate this risk in such individuals.…”

“…For tacrolimus cotreated transplant recipients, 7 of 11 cohorts (comprising 1373 of 1696 individuals, 81.0%) revealed a statistically significant association. 41,85,89,91,93,97,98 Two further cohorts reported a trend (11.9% of individuals). 80,94 This left 2 cohorts (7.2% of individuals).…”

“…A statistically significant relationship between MPA AUCt 0-12 and rejection was evident in 20 of the 27 cohorts (comprising 3382 of 3794 individuals, 89.1%). 26,31,35,41,74,77-79,81,83-87,89,91-93,95-98 An additional 3 studies showed a trend in favor of this association (5.7% of individuals), 80,90,94 leaving only 4 cohorts (5.1% of individuals) without association. 75,76,82…”

“…In “OPERA,” TCI was effective in maintaining MPA exposure target and reducing within-group PK variability, beyond the initial “dose intensification” period. Notably, 3 other trials of MPA “dose intensification” (without subsequent TCI), in standard or higher-risk recipients, revealed either a significant reduction in rejection 98,116 or strong trend, 91 showing that this intervention alone can impact outcomes. In contrast, OPERA revealed no efficacy benefit at 3 months (and less tolerance).…”

“…However, the validity of MPA AUCt 0-12 as a biomarker for drug exposure, causally linked to drug effect, will still apply with different drug combinations or populations, although exposure target may differ. Second, precision dosing aims to maximize benefits and minimize toxicities: in contemporary cohorts, there remains MPA underexposure associated with rejection, 41,89,91,93,97,98 dose-dependent toxicities, 129,130,134 and overexposure associated with toxicities, 80,94,99,104,105 highlighting a potential value of TCI.…”